The effects of lead (Pb) on the developing brain have been studied for decades but there are still gaps in our understanding of how this environmental toxicant influences brain development and function. The modification of Pb's influences on nervous system development and function by genetic background and the manner in which Pb interacts with the genome to produce long-lasting behavioral and other effects are mostly unknown. These research questions are the basis of the parent grant associated with this competitive revision application. However, to more fully understand Pb-genome interactions, effects on the epigenome also need to be studied. In particular, this competitive revision application will focus in general on genome-wide Pb-induced alterations in methylation and in particular, on changes in methylation state and expression of MeCP2 (a DNA binding protein involved in transcriptional regulation of a multitude of genes) and critically involved in neuronal maturation and plasticity as well as a variety of cognitive and behavioral disorders including Rett syndrome, autism, mental retardation, ADHD, and learning disabilities. Since recent studies suggest that environmental toxicants can affect the integrity of the genome through effects on epigenetic mechanisms, the extent to which this occurs with different levels and types of Pb exposure need to be studied. Thus, the research proposed in this application has the following specific aim: Specific Aim. Assess the extent to which different types and levels of developmental lead exposure result in epigenetic influences on DNA methylation and MeCP2 expression/methylation in particular and the extent to which these effects correlate with gender and behavioral outcome. These studies will examine the extent to which different types and levels of lead exposure in male and female animals influence DNA methylation on a genome-wide basis and the extent to which there is aberrant MeCP2 promoter methylation and MeCP2 protein expression in the hippocampus, a brain regions known to be functionally affected by developmental lead exposure. We will then correlate these findings with behavioral outcomes. Our hypothesis is that lead exposure leads to a neurodevelopmental disorder, fundamentally, a disorder of plasticity, related to altered epigenetic gene regulation (i.e., alterations in DNA methylation) and that these effects may vary with gender. PUBLIC HEALTH RELEVANCE: The proposed research will provide new data on the effects of developmental lead exposure on epigenetic modifications (i.e., modifications to genes that do not involve changes in the DNA sequence). Recent reports suggest that environmental toxicants may affect the integrity of the genome and can do so through epigenetic mechanisms. Understanding effects of developmental lead exposure on the epigenome may help to tie together basic, clinical and epidemiological data showing effects on a multitude of diverse physiological processes and outcomes including impairments in neuronal structure and functioning and impairments in cognitive, social, language and motor skills that persist into adulthood.